Sleep-dependent modulation of transplanted circuit integration

The National Institute of Neurological Disorders and Stroke awarded Northern California Institute For Research And Education, Inc. (NCIRE) $414,464 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to support research on sleep-dependent modulation of transplanted neural circuits for stroke recovery.

The project characterizes the integration of human induced pluripotent stem cell (iPSC)-derived neurons transplanted into stroke-affected mouse brains, studying neural dynamics during sleep and wake states using dual-color calcium imaging to identify sleep-specific oscillations that promote synaptic plasticity and functional connectivity between transplanted and host neurons. A second research aim compares open-loop versus closed-loop electrical stimulation during sleep and behavior on neural coupling, integration, and motor recovery, hypothesizing that closed-loop stimulation aligned with intrinsic neural activity enhances recovery. The work employs wearable dual-color calcium imaging miniscopes and closed-loop stimulation interfaces to monitor and modulate neural activity in real-time, with the goal of identifying mechanisms supporting neural integration and informing personalized, activity-dependent therapies for stroke rehabilitation.

NCIRE, a San Francisco-based nonprofit research organization, serves as the prime recipient. Performance occurs in San Francisco, California. The period of performance runs September 1, 2026, through August 31, 2028. The assistance type is a Project Grant.

Abstract

Stroke is the leading cause of long-term disability worldwide, leaving many survivors with severe motor impairments and paralysis. Current treatments do not address the restoration of lost neural circuits, highlighting the urgent need for innovative therapeutic strategies. This project aims to optimize a novel biohybrid neural interface that combines human induced pluripotent stem cell (IPSC)-derived neurons with in vivo calcium imaging and neuromodulation techniques to restore motor function after stroke. Our first aim focuses on characterizing the integration of transplanted neurons into the host brain by studying neural dynamics during sleep and wake states in freely behaving stroke mice. Leveraging dual-color calcium imaging, we will identify sleep-specific oscillations that promote synaptic plasticity and functional connectivity between transplanted and host neurons. In our second aim, we will compare the effects of open - loop versus closed-loop electrical stimulation during sleep/behavior on cross-area neural coupling, integration, and motor recovery, hypothesizing that closed-loop stimulation aligned with intrinsic neural activity will enhance recovery. This research employs cutting-edge technologies, including a wearable dual-color calcium imaging miniscope and a closed-loop stimulation interface, to monitor and modulate neural activity in real-time. The proposed work will provide critical insights into the mechanisms of neural integration and recovery, paving the way for personalized, activity-dependent therapies for stroke rehabilitation. The outcomes of this project will address a significant GAP in stroke treatment, offering a novel approach to repair damaged neural circuits and improve quality of life for millions of individuals. This aligns with the NIH mission to advance knowledge and develop innovative therapies to reduce the burden of neurological diseases.